The ability of the copper (Cu) exporters ATP7A and ATP7B to regulate tumor cell sensitivity to the platinum-containing drugs by altering their intracellular sequestration and efflux has now been demonstrated in multiple experimental systems. The overall goal of this project is to determine the mechanism by which ATP7A and ATP7B mediate the efflux of cisplatin, carboplatin and oxaliplatin from ovarian carcinoma cells. Our hypothesis is that at clinically relevant concentrations, the platinum drugs enter the cell, are distributed to various subcellular compartments and are exported from the cell using transporters and chaperones that have evolved to control Cu homeostasis. A corollary to this hypothesis is that, as for Cu, these PI-type ATPases function to detoxify the Pt drugs by sequestering them into or onto vesicles of the secretory pathway that are eventually exported from the cell.
The specific aims are to: 1) determine whether ATP7A and ATP7B bind and transport cisplatin, carboplatin and oxaliplatin into secretory vesicles; 2) investigate the ability of the Pt drugs to bind to the Cu-binding motif in the metal binding sequences of ATP7A, ATP7B and ATOX1 proteins; and, 3) determine whether the Cu chaperone ATOX1 is essential to the ability of ATP7A and ATP7B to mediate Pt drug resistance, sequestration, and export in living cells. Careful dissection of the mechanism by which the Cu efflux transporters modulate the export of the Pt drugs is expected to offer insight into why cisplatin, carboplatin and oxaliplatin differ in their efficacy and toxicity, and to identify strategies for improving the therapeutic index of these agents. These studies will also further elucidate the mechanisms that mediate resistance to this important class of chemotherapeutic agents and suggest clinically relevant strategies for reversing resistance. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA095298-04
Application #
6966105
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Wolpert, Mary K
Project Start
2002-05-01
Project End
2010-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$231,770
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Huang, Carlos P; Fofana, Mariama; Chan, Jefferson et al. (2014) Copper transporter 2 regulates intracellular copper and sensitivity to cisplatin. Metallomics 6:654-61
Quail, Jacob F; Tsai, Cheng-Yu; Howell, Stephen B (2014) Characterization of a monoclonal antibody capable of reliably quantifying expression of human Copper Transporter 1 (hCTR1). J Trace Elem Med Biol 28:151-9
Liberman, Alexander; Wu, Zhe; Barback, Christopher V et al. (2013) Color Doppler ultrasound and gamma imaging of intratumorally injected 500 nm iron-silica nanoshells. ACS Nano 7:6367-77
Gu, Luo; Hall, David J; Qin, Zhengtao et al. (2013) In vivo time-gated fluorescence imaging with biodegradable luminescent porous silicon nanoparticles. Nat Commun 4:2326
Safaei, Roohangiz; Adams, Preston L; Mathews, Ryan A et al. (2013) The role of metal binding and phosphorylation domains in the regulation of cisplatin-induced trafficking of ATP7B. Metallomics 5:964-72
Tsigelny, Igor F; Sharikov, Yuriy; Greenberg, Jerry P et al. (2012) An all-atom model of the structure of human copper transporter 1. Cell Biochem Biophys 63:223-34
Safaei, Roohangiz; Adams, Preston L; Maktabi, Mohammad H et al. (2012) The CXXC motifs in the metal binding domains are required for ATP7B to mediate resistance to cisplatin. J Inorg Biochem 110:8-17
Tsai, Cheng-Yu; Finley, J Cameron; Ali, Sameh S et al. (2012) Copper influx transporter 1 is required for FGF, PDGF and EGF-induced MAPK signaling. Biochem Pharmacol 84:1007-13
Pohaku Mitchell, Kristina K; Liberman, Alexander; Kummel, Andrew C et al. (2012) Iron(III)-doped, silica nanoshells: a biodegradable form of silica. J Am Chem Soc 134:13997-4003
Liberman, Alexander; Martinez, H Paul; Ta, Casey N et al. (2012) Hollow silica and silica-boron nano/microparticles for contrast-enhanced ultrasound to detect small tumors. Biomaterials 33:5124-9

Showing the most recent 10 out of 46 publications